Nature Medicine
9, 1498 - 1505 (2003)
Published online: 2 November 2003; | doi:10.1038/nm954
Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulationKenyatta Cosby1, Kristine S Partovi2, Jack H Crawford3, Rakesh P Patel3, Christopher D Reiter2, 4, Sabrina Martyr2, 4, Benjamin K Yang2, Myron A Waclawiw5, Gloria Zalos1, Xiuli Xu6, Kris T Huang7, Howard Shields6, Daniel B Kim-Shapiro6, 7, Alan N Schechter4, Richard O Cannon III1, 8
& Mark T Gladwin2, 4, 81
Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B15 Bethesda, Maryland 20892, USA. 2
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, 10 Center Drive, Building 10, Room 7D43 Bethesda, Maryland 20892, USA. 3
Department of Pathology, Center for Free Radical Biology, Biomedical Research Building II, Room 307, 901 19th Street South, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. 4
Laboratory of Chemical Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9N307, Bethesda, Maryland 20892, USA. 5
Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, 6701 Rockledge Drive, Bethesda, Maryland 20892, USA. 6
Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109-7507, USA. 7
Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1022, USA. 8
These authors contributed equally to this work.
Correspondence should be addressed to Richard O Cannon III cannonr@nih.gov or Mark T Gladwin mgladwin@nih.govNitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36  mol/min into the forearm brachial artery resulted in supra- and near-physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated hemoglobin and, to a lesser extent, S-nitroso-hemoglobin. NO-modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO-modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation.
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